This invention is concerned with compounds which are spiro-indolines of general structure: 
The invention is also concerned with the use of these novel compounds to selectively antagonize the Y5 receptors and thereby inhibit obsessive food intake and the resulting obesity and complications associated therewith.
The invention is also concerned with pharmaceutical formulations comprising one of the compounds as active ingredient.
The invention is further concerned with processes for preparing the compounds of this invention.
Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system. NPY and its relatives elicit a broad range of physiological effects through activation of at least six G protein-coupled receptor subtypes known as Y1, Y2, Y3, Y4, Y5 and Y6. The Y5 subtype was isolated, characterized and reported recently in U.S. Pat. No. 5,602,024 (WO 96/16542).
The cited WO 96/16542 also reports the discovery of chemical compounds which bind selectively to the Y5 receptor and which act as antagonists of the Y5 receptor, several of which were shown to inhibit food intake in rats.
Now with the present invention there is provided a class of compounds characterized as spiro-indolines, which are useful in the treatment, control or prevention of diseases, disorders or conditions mediated by activation of the Y5 receptor. These compounds are, thus, useful in the treatment of obesity in man or animals and in conditions caused by or exacerbated by obesity.
The compounds of this invention are represented by the compound of structural formula I: 
or a pharmaceutically acceptable salt thereof, wherein;
V, W, X and Z are independently selected from CH and N;
R1 is H, C1-3 alkyl, C1-3 alkoxy, F, or Cl;
R2 is S(O)nR6, COR6 or CHO, wherein
n is 0, 1 or2; and
R6 is N(R3)2 or C1-3 alkyl;
R3 is independently H or C1-3 alkyl;
Ar is aryl or heteroaryl;
R4 and R5 are independently selected from:
(1) hydrogen,
(2) aryl, either unsubstituted or substituted with
(a) halo
(b) C1-3 alkoxy,
(c) xe2x80x94N(C1-3 alkyl)2,
(d) C2-4 alkanoyl, or
(e) aryl,
(3) nitro,
(4) C1-5 alkyl,
(5) C1-5 alkoxy,
(6) hydroxy-C1-3 alkyl,
(7) carboxy,
(8) halo,
(9) C1-5 alkylthio,
(10) C1-5 alkoxycarbonyl,
(11) pyridylcarbonyl,
(12) benzoyl,
(13) phenyl-C1-3 alkoxy,
(14) pyridyl, either unsubstituted or substituted with C1-3 alkyl or C1-3 alkoxy,
(15) C3-6 cycloalkyl,
(16) oxazolyl,
(17) thiazolyl,
(18) triazolyl,
(19) phenoxy or
(20) C2-6 alkanoyl.
The term xe2x80x9calkylxe2x80x9d means linear and branched structures and combinations thereof, containing the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl and the like.
xe2x80x9cCycloalkylxe2x80x9d means a hydrocarbon having the indicated number of carbon atoms, containing one or more rings. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d includes F, Cl, Br, and I unless otherwise specified.
xe2x80x9cHeteroarylxe2x80x9d is a 5- or 6-membered aromatic heterocycle, or a benzo- or pyrido-fused version thereof, all having, besides carbon atoms, 1 to 3 hetero atoms selected from N, O, and S as atom(s) constituting the ring. Examples thereof include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, benzothienyl, benzofuranyl, indolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl, pyridothiazolyl, quinolyl, isoquinolyl or triazolyl.
xe2x80x9cArylxe2x80x9d is phenyl or naphthyl.
xe2x80x9cAlkoxyxe2x80x9d means linear and branched structures and combinations thereof, containing the indictaed number of carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, s- and t-butoxy, pentoxy, and the like.
xe2x80x9cAlkanoylxe2x80x9d means linear and branched structures and combinations thereof, containing the indicated number of carbon atoms. Examples of alkanoyl groups include, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.
One embodiment of the novel compounds of this invention is that wherein Ar is phenyl of structural formula I(a) 
or a pharmaceutically acceptable salt thereof.
A class of compounds within this embodiment is that wherein X and Z are both nitrogen, and V and W are both xe2x80x94CHxe2x95x90.
A sub-class is that wherein R2 is xe2x80x94SO2(C1-3 alkyl) or xe2x80x94SO2NH2.
A sub-sub-class of the compounds of this embodiment is that wherein R4 and R5 are independently selected from: phenyl, pyridyl, benzoyl, halophenyl, phenoxy, C1-5 alkylpyridyl, benzhydryl, phenyl-C1-3 alkoxy, NO2, C2-4 alkanoyl, halo, C1-5 alkoxy, C1-3 alkoxycarbonyl, C1-5 alkylthio, triazolyl, carboxy, hydrogen, C1-5 alkyl, pyridylcarbonyl, and C1-3 alkoxyphenyl.
Typical of the compounds of this sub-sub-class are those wherein R2 and phenyl(R4)(R5) are as shown in the following TABLE I:
A second embodiment of the compounds of this invention is that wherein Ar is a 5- or 6-membered heteroaryl having, besides carbon atoms, 1 to 3 hetero atoms selected from N, O and S as atoms constituting the ring, or benzo- or pyrido-fused versions thereof, of structural formula I(b); 
or a pharmaceutically acceptable salt thereof.
A class of compounds within this embodiment, is that wherein X and Z are both nitrogen, and V and W are both xe2x80x94CHxe2x95x90.
A sub-class is that wherein R2 is xe2x80x94SO2(C1-3 alkyl) or xe2x80x94SO2N(C1-3 alkyl)2.
A sub-sub-class of compounds within this embodiment is that wherein the heteroaryl group, Ar, is selected from: thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, benzothiazolyl, oxazolyl, pyridothiazolyl, benzoxazolyl, quinolyl, pyrazinyl, thienyl, isoxazolyl, pyrimidinyl, benzimidazolyl, oxadiazolyl and imidazolyl.
Typical of the compounds of this sub-sub-class are those wherein R2 and Ar(R4)(R5) are as shown in TABLE II.
A third embodiment of the compounds of this invention is that wherein one of X and Z is N and the other is xe2x80x94CHxe2x95x90 of structural formula 1(c): 
or a pharmaceutically acceptable salt thereof.
A class of compounds within this embodiment is that wherein X is N, Z is xe2x80x94CHxe2x95x90 and V and W are both xe2x80x94CHxe2x95x90
Typical of the compounds within this class are those shown in TABLE III:
A second class of compounds within this embodiment is that wherein X is xe2x80x94CHxe2x95x90, Z is N and V and W are both xe2x80x94CHxe2x95x90.
Typical of the compounds within this second class are those shown in TABLE IV:
A fourth embodiment of the compounds of this invention is that wherein R2 is xe2x80x94COR6 of structural formula I(d): 
or a pharmaceutically acceptable salt thereof.
A class of compounds within this embodiment is that wherein X and Z are both N and V and W are both xe2x80x94CHxe2x95x90.
Typical of the compounds within this embodiment are those shown in TABLE V:
A fifth embodiment of the compounds of this invention is that wherein one of V or W is nitrogen (N) and the other is xe2x80x94CHxe2x95x90 of formula I(e): 
A class of compounds within this embodiment is that wherein R1 and R3 are H and X and Z are both nitrogen.
A sub-class of compounds within this class is that wherein R2 is xe2x80x94SO2CH3.
Typical of the compounds within this sub-class are those depicted in the following TABLE VI:
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to include such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic and organic acids and bases.
When the compound of the present invention is acidic, salts may be prepared from inorganic bases such as aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine, histidine, hydrabamine, N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, adipic, aspartic, 1,5-naphthalenedisulfonic, benzenesulfonic, benzoic, camphorsulfonic, citric, 1,2-ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic, hydriodic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, 2-naphthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, pivalic, propionic, salicylic, stearic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, undecanoic, 10-undecenoic, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, methanesulfonic, phosphoric, sulfuric and tartaric acids. It will be understood that in the materials which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
Another aspect of this invention are the processes used to prepare the novel compounds.
Compounds in which X and Z are both nitrogen are prepared by the general procedures outlined in Scheme I. 
The Cbz spiroindoline 3 is prepared according to the method described in Tetrahedron 53, 10983-10992 (1997).. In one procedure 3 is treated with a reagent R2Cl, wherein R2 is as defined above, in the presence of a base such as a tertiary amine, including triethylamine (Et3N), diisopropylethylamine (DIEA), or pyridine, followed by removal of the carbobenzyloxy (Cbz) protecting group by hydrogenolysis with hydrogen over a noble metal catalyst at room temperature and pressure in a lower alcohol such as methanol or ethanol, or an etherial solvent such as diethyl ether of tetrahydrofuran (THF) or mixtures thereof to give 4 following the methods described in Tetrahedron 53 10983-10992, (1997) wherein the preparation of 4 is described wherein R2 is xe2x80x94SO2CH3.
Compound 4 (with R2 protected if necessary) is then treated with a phenyl carbamate of structure PHOCONHxe2x80x94Ar(R4)(R5) in the presence of a tertiary amine in an organic solvent such as a haloalkane such as chloroform, methylene chloride, ethylene dichloride or the like at reflux temperature or in the presence of NaOH in H2O/DMSO, until the reaction is complete, usually in about xc2xd to about 3 hours followed by deprotection of the R2 group if necessary, to provide the Compound I(R3xe2x95x90H).
In the above procedures, the phenyl carbamates are prepared by reaction of the corresponding amines of structure NH2xe2x80x94Ar(R4)(R5) which are commercially available or readily synthesized, with phenyl chloroformate in pyridine at room temperature as described in Example I below.
Alternatively, Compound I is prepared by treatment of 4 with an isocyanate of structure OCNxe2x80x94Ar(R4)(R5) in a chlorinated alkane at reflux temperature until the reaction is complete in about 4 to about 12 hours.
Compound I can also be prepared by conducting the above procedures in the reverse order. The indoline nitrogen of 3 is protected with Boc by treatment with di-tert-butyl dicarbonate in the presence of a base, such as, NaOH or triethyl amine, in an inert solvent such as aqueous dioxane or methanol and the Cbz group is hydrogenolyzed with hydrogen and a noble metal catalyst to give 5. Treatment of 5 with either the phenyl carbamate or isocyanate described earlier provides 6 which upon deprotecting with a strong acid such as hydrochloric or trifluoroacetic acid in an inert solvent such as ethyl acetate or methylene chloride and treatment with R2Cl in the presence of a tertiary amine as described above provides Compound I( R3xe2x95x90H).
Compounds of this invention are antagonists of the Y5 receptor and as such are useful for the prevention and treatment of disorders or diseases associated with the Y5 receptor sub-type, preferably for the treatment of feeding disorders such as obesity, anorexia nervosa and bullimia nervosa, and other abnormal conditions, such as diabetes, hypertension, hyperlipemia, hypercholesterolemia, congestive heart failure, renal dysfunction, sexual/reproductive disorders, depression, anxiety, shock, epileptic seizure, memory loss, sleep disturbance, pain, migraine, cerebral hemorrhage, nasal congestion, gastrointestinal disorders, arthritis and immunodeficiency syndrome.
The Y5 antagonists of this invention may also be used in combination with other anti-obesity agents for increased efficacy in the prevention and treatment of obesity Such agents would include, but not be limited to: sibutramine; dexenfluramine; leptin; growth hormone secretagogues such as those disclosed and specifically described in U.S. Pat. No. 5,536,716; melanocortin agonists such as Melanotan II; Beta-3 agonists such as those disclosed and specifically described in patent publications WO94/18161, WO95/29159, WO97/46556, WO98/04526 and WO98/32753; 5HT-2 agonists; orexin antagonists; melanin concentrating hormone antagonists; galanin antagonists; CCK agonists; GLP-1 agonists; corticotropin-releasing hormone agonists; and Y1 antagonists.
The method of treatment of this invention comprises a method of antagonizing the Y5 receptor and treating Y5 receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the Y5 receptor in preference to the other NPY receptors.
Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, obesity may be effectively prevented or treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
For the treatment of any of these Y5 receptor mediated diseases, compounds of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
The novel pharmaceutical compositions of this invention containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Compounds of the invention may also be administered in the form of a suppository for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The following Examples describe the laboratory synthesis of specific compounds of the invention and are not meant to limit the scope of the invention in any way with respect to compounds or processes. It is understood that, although specific reagents, solvents, temperatures and time periods are used, there are many possible equivalent alternatives that can be used to produce similar results. This invention is meant to include such equivalents.
Abbreviations used herein have the following meanings: